The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems in both experimental animals and humans. Several immune system products, such as the inflammatory cytokines, tumor necrosis Factor-alpha, interleukin-1, and interleukin-6 activate the hypothalamic-pituitary-adrenal (HPA) axis and through it suppress and restrain the inflammatory/immune response. Interleukin-6 is particularly potent in humans, stimulating not only ACTH and cortisol but also arginine-vasopressin (AVP) secretion. Plasma interleukin-6 is elevated in glucocorticoid deficiency states and after exercise. Elevations of interleukin 6 in infectious, inflammatory, and traumatic states may explain the pathogenesis of the Syndrome of Inappropriate AVP Secretion observed in these states. The glucocorticoid antagonist RU 486 potentiated the inflammatory/immune response to a standard inflammatory stimulus in intact animals, suggesting that endogenous glucocorticoids exert anti-inflammatory/immunosuppressive effects at physiological levels. We recently demonstrated that corticotropin releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids and somatostatin suppress, and RU 486 markedly augments local secretion of immune CRH at an inflammatory site. Immune CRH was found in the ovary and endometrium, where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. RU 486 allowed the identification of a central nervous system defect in rats prone to arthritis. In these animals the glucocorticoid response to stress-mediators is inadequate to restrain the immune system following an inflammatory insult. The actual defect is global and located at the level of the hypothalamic CRH neuron, which responds poorly to all its known stimulants, including several cytokines, as well as serotonin, acetylcholine and norepinephrine. This pathophysiologic mechanism is novel and of relevance to human arthritis and other autoimmune diseases. Patients with rheumatoid arthritis have defective pituitary-adrenal axis responses to inflammatory stimuli and produce excessive amounts of immune CRH in their inflamed joints. Patients with fibromyalgia have a slight hypofunction of their hypothalamic-pituitary-adrenal axis revealed by CRH testing and measurements of urinary free cortisol excretion. Patients with multiple sclerosis have mild hypercortisolism, which is sustained by chronic hypothalamic AVP rather than CRH hypersecretion. The human CRH gene contains estrogen-responsive elements in its promoter region providing an explanation for the sexual dimorphism in the incidence of autoimmune/inflammatory disease. CRH antagonists may be useful in the treatment of autoimmune/inflammatory diseases. We found elevated levels of AVP in rats prone to arthritis and patients with rheumatoid arthritis. AVP potentiated the inflammatory response of rats, suggesting that this peptide also participates in inflammation.